Atherosclerotic peripheral arterial disease (PAD) affects 8-10 million people in the United States. Symptomatic PAD leads to a marked impairment in quality of life and is associated with increased mortality. Conventional risk factors for atherosclerosis explain less than 50% of variation in measures of PAD. The aim of this proposal is to elucidate new biomarkers of PAD. Results of the proposed investigation have the potential to enhance our understanding of the pathogenesis of PAD and to promote development of preventive and therapeutic strategies. The Genetic Epidemiology Network of Arteriopathy (GENOA) is completing linkage and association studies to identify genes influencing blood pressure and the cerebral, cardiac, and renal complications of hypertension in African-American and non-Hispanic white sibships ascertained through hypertensive sibling pairs. This study will extend those efforts by identifying novel biochemical and genetic factors contributing to presence and extent of PAD, which is assessed in GENOA by measurement of the ankle-brachial index. The ankle-brachial index is a simple noninvasive measure that is continuously distributed and bears a direct and incrementally graded relationship to the severity of PAD. The aims of the proposal are as follows: Aim 1: To determine using linear regression analyses whether novel biochemical factors influencing the atherosclerotic process can improve the prediction of an established quantitative measure of peripheral arterial disease - the ankle-brachial index - beyond what is possible with conventional risk factors in 1200 African-American and 1200 non-Hispanic white GENOA participants. Aim 2: To determine using variance components linkage analyses whether any of 387 polymorphic tandem repeat marker loci spanning the genome are linked to genes influencing interindividual differences in the ankle-brachial index in more than 1400 African-American and 1400 non-Hispanic white GENOA sibling pairs. Aim 3: To determine using family-based association analyses whether diallelic polymorphisms in candidate genes, including those identified as positional candidates in Aim 2 as well as those involved in conventional and novel risk factor pathways (from aim 1), influence interindividual differences in the ankle-brachial index in 1200 African-American and 1200 non-Hispanic white GENOA participants.